Fight Aging!

Senescent cells are created constantly throughout life, largely as somatic cells reach the Hayflick limit on replication, but also in response to cell damage and stress. In youth, the immune system rapidly removes these cells. With age, immune clearance falters and lingering senescent cells grow in number in tissues throughout the body. These cells secrete a potent mix of pro-inflammatory signals that can be beneficial in the short term, drawing the attention of the immune system to potential problems, but this signaling becomes disruptive to tissue structure and function when sustained over the long term. The greater the number of senescent cells, the worse the consequent chronic inflammation and harmful outcomes. This is a significant contribution to degenerative aging.

While the development of therapies to selectively destroy senescent cells is very much an ongoing concern, with the first few drugs in clinical trials for several years now, finding a convenient measure to assess the burden of cellular senescence has proven to be harder than expected. One can always take a tissue biopsy and count senescent cells via histology, but this is far from convenient. For all that these cells secrete a wide range of well-known inflammatory signals, the amounts in circulation that can be assessed via a blood sample do not correlate well to the burden of senescent cells. There are too many other sources and sinks operating, muddying the waters. Similarly, directly assessing senescence in white blood cells from a blood sample doesn't map well to the global burden of such cells in tissues, as the immune system is subject to stresses that are very different from those associated with cells in tissues.

Still, it seems plausible that there must be some useful measure of the burden of senescence that can be obtained from circulating signal molecules. In today's open access paper, researchers put forward IL-23R as a candidate for that molecule. If validated, this should help to speed the development of more effective senolytic therapies to clear senescent cells from the aged body and brain.

IL-23R is a senescence-linked circulating and tissue biomarker of aging

Characteristic properties of senescent cells include upregulation of cell cycle regulatory proteins, including p16ink4a, the senescence-associated secretory phenotype (SASP), and activation of senescent cell anti-apoptotic pathways (SCAPs). The SASP is cell-type- and context-specific and can confer adverse changes to local tissue environments and systemic organs. Use of the p16-InkAttac transgenic model, which permits systemic clearance of p16-positive cells through a temporally controlled suicide gene, has demonstrated that senescent cell deletion alleviates features of age-related pathology in several organs, including kidney, adipose, skeletal muscle, eye, heart, and brain. A recent comparison of cell-type-specific versus whole-body transgenic targeting of p16-postitive cells demonstrated greater benefits in aged bone composition following systemic clearance, which supports the notion that the adverse influence of senescent cells and the SASP results from both local and distant signaling.

Despite considerable senolytic testing underway in preclinical models and humans, understanding of the comparative effects of senolytic drugs and senescent cell targeting efficiency across tissues is limited. The central goal of this study was to identify age- and senescence-related plasma and tissue biomarkers that are responsive to senotherapeutic intervention. We assessed system-wide profiles of senescence, SASP, and inflammatory biomarkers in aging and their alteration by clinically relevant senolytic compounds versus transgenic p16-InkAttac senescent cell targeting in mice.

We discovered that the abundance of IL-23R, CCL5, and other proteins showing age-dependent increases in circulation were reduced by senotherapeutic agents. CA13 decreased in aged plasma, and senolytics restored this factor toward youthful levels. In secretory tissues, gene expression of Il23r and Ccl5 coincided with expression of senescence markers and aged plasma protein abundance in vivo, and these factors were significantly upregulated and secreted by senescent cells in vitro. Our results suggest that senescent cells in aged kidney, liver, and spleen are viable sources of these aging biomarkers in blood circulation. Among the drugs tested, venetoclax suppressed age-related changes in the greatest number of circulating and tissue biomarkers in aged mice. In human plasma, we discovered that IL-23R abundance increased with age in both women and men.